Analysis of Cytogenetic Abnormalities in Iranian Patients with Syndromic Autism Spectrum Disorder: A Case Series

Objective Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric group of pervasive developmental disorders mainly diagnosed through the complex behavioral phenotype. According to strong genetic involvement, detecting the chromosome regions and the key genes linked to autism can help to elucidate its etiology. The present study aimed to investigate the value of cytogenetic analysis in syndromic autism and find an association between autism and chromosome abnormalities. Materials & Methods Thirty-six autistic patients from 30 families were recruited, clinically diagnosed with the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). The syndromic patients with additional clinical features (including development delay, attention deficit, hyperactivity disorder, seizure, and language and intellectual impairment) were selected due to elevating the detection rate. Cytogenetics analysis was performed using GTG banding on the patients’ cultured fibroblasts. Moreover, array-comparative genomic hybridization (CGH) was also performed for patients with a de novo and novel variant. Results Karyotype analysis in 36 syndromic autistic patients detected chromosomal abnormalities in 2 (5.6%) families, including 46,XY,dup(15)(q11.1q11.2) and 46,XX,ins(7)(q11.1q21.3)dn. In the latter, array-CGH detected 3 abnormalities on chromosome 7, including deletion and insertion on both arms: 46,XX,del(7)(q21.11q21.3),dup(7)(p11.2p14.1p12.3)dn. Conclusion We reported a novel and de novo cytogenetic abnormality on chromosome 7 in an Iranian patient diagnosed with syndromic autism. However, the detection rate in syndromic autism was low, implying that it cannot be utilized as the only diagnostic procedure.


Introduction
Autism spectrum disorder (ASD) is a group of childhood neurological and developmental disabilities described by the triad of abnormal social interest, communication deficit, and restricted/ repetitive behavior with a strong hereditary basis (1,2). Because of the wide range of severity and types, currently, it is assigned as a spectrum disorder, not only clinically but also genetically. Depending on the presence or absence of several forms of dysmorphic features and neurobehavioral manifestations, ASD is categorized as a syndromic or non-syndromic (idiopathic) disorder, respectively. The causes of this major public health problem are still mostly unknown; however, there may be multiple types of causes, mostly comprising environmental and genetic causes (3). Based on twin studies using a quantitative meta-analysis approach, the heritability of ASD is estimated between 64% and 91%, implying a strong genetic effect (4).
Syndromic autism is characterized as one of the neurodevelopmental disorders, accompanying further medical aspects that are frequently associated with chromosomal abnormalities. There is convincing evidence of a principally genetic role in autism and insignificant shared environmental impacts; however, the etiology remains largely unexplained in most cases (4).
From the genetic point of view, ASD is highly heterogeneous and frequently related to chromosomal abnormalities as it is detectable in some syndromes such as fragile X syndrome and tuberous sclerosis (5-7). Microscopically noticeable chromosomal modifications have been explained in about 5% of cases (8). Almost every chromosome has been proved to be linked to autism (9). Some chromosomal aberrations have been frequently reported; the most frequent abnormalities are 15q11-q13 duplications, as well as 2q37, 22q11.2, and 22q13.3 deletions (10).

Materials & Methods
The current study recruited 36 patients from 30 families with at least one of the children having

Results
Thirty-six Iranian patients with syndromic ASD, including 30 males and 6 females, from Imam Hossein Hospital, met the diagnostic criteria of autistic disorder and karyotyping analysis. All general and clinical data about these cases are available in Table 1. EEG and cerebral MRI showed no anomalies.

Patients' electroencephalography (EEG) and
Thus, ASD level 1 was suspected, and the diagnosis was confirmed using DSM-5 criteria by a pediatric psychiatrist.
Twenty metaphase spreads were analyzed, and interstitial duplication within the long arm of chromosome 15 from bands q11.1 to q11.2 was observed in all metaphases ( Figure 2).

Case 2
This case, a 9-year-old girl, is the only child of consanguineous and healthy parents born by cesarean delivery. Mother had a normal pregnancy.
Ultrasonic examinations did not show any abnormality.
The patient has a speech delay. Her EEG and MRI were completely normal, and she had no seizure.
She has a mild intellectual disability and ADHD.

In Conclusion
We concluded that the karyotype could help syndromic ASD patients to distinguish genetic causes as one of the first-tier tests--but not only.

Acknowledgement
Sincere gratitude to the families for their participation in this study.